The inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown to stimulate HIV-1 replication in both chronically and acutely infected T-lymphocytes and monocytes. The activation of the HIV-Long Terminal Repeat (HIV-LTR) and subsequent increase in virus production is linked to TNF activation of the cellular transcription factor, NF-kB. We have tested the ability of two forms of soluble recombinant type 1 (p80) TNF receptor to inhibit TNF-induced HIV activation in vitro. One form of the receptor is a monomer containing the entire 234 residues of the extracellular (ligand-binding) portion of p80. A second form is a homodimer chimeric protein containing these same residues fused to a truncated human IgG(l) immunoglobulin chain, and thus resembles a bivalent antibody without light chains. These recombinant proteins were tested for their ability to inhibit TNF-alpha-induced expression of HIV-1 in chronically infected human cell lines as determined by viral reverse transcriptase activity. We also examined the ability of the soluble receptors to limit the activation of HIV-LTR transcription. The soluble TNF receptor dimer was most effective at blocking the TNF-alpha-induced expression in both monocytic and lymphocytic cell lines. The ratio of receptor to TNF-alpha was critical, with optimal inhibition requiring a 10-fold excess of receptor. Monomeric receptor was less effective at blocking and, at times, was capable of augmenting the activity of TNF-alpha. Thus, our data suggests that TNF-alpha-induced HIV-1 expression can be limited in vitro using a dimeric form of the TNF receptor at specific ratios in excess of TNF-alpha.